rs879254520

Positions:

• chr19-11105326-G-C
• chr19-11105326-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.420G>C​(p.Glu140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E140K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 2.05

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PS1: Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a turn (size 4) in uniprot entity LDLR_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-11105326-G-C is Pathogenic according to our data. Variant chr19-11105326-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105326-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.420G>C	p.Glu140Asp	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.420G>C	p.Glu140Asp	missense_variant	4/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jun 05, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 23, 2017	This c.420G>C (p.Glu140Asp) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11754108, 20145306, 22698793, 23680767). A different variant at the same residue (p.Glu140Lys) has also been described in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 21722902, 23375686) The p.Glu140Asp variant occurs within the low-density lipoprotein receptor repeat class A domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.420G>C variant is not detected in the general population and glutamate at position 140 of the LDLR protein is highly evolutionarily conserved. The c.420G>C (p.Glu140Asp) variant in the LDLR gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	LDLR: PS4, PM1, PM2, PM5, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E119D; This variant is associated with the following publications: (PMID: 10081189, 11754108, 31447099, 29261184, 11524740, 17094996, 20145306, 22698793, 34037665, 32770674, 33489595, 33418990, 33740630) -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 140 of the LDLR protein (p.Glu140Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11754108, 17094996, 20145306). ClinVar contains an entry for this variant (Variation ID: 251216). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Glu140 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11668627, 21722902, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 23, 2018

The p.Glu140Asp variant in LDLR has been reported in the heterozygous state in at least 10 individuals with familial hypercholesterolemia (FH; Kuhrova 2002, Tosi 2007, Chmara 2010, Tichy 2012, Vandrovcova 2013, Duskova 2011). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 251216) and was absent in large population studies. Computational prediction tools and conservation analysis suggest that the p.Glu140Asp variant may impact the protein. Additionally, different amino acid changes at this position have been reported in individuals with FH (Stenson 2017), including the p.Glu140Lys variant which has been classified as likely pathogenic by other clinical laboratories (ClinVar variation ID 251213), suggesting that changes at this amino acid position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu140Asp variant is likely pathogenic. ACMG/AMP applied: PS4_Moderate, PM5, PM2, PP3. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The p.E140D pathogenic mutation (also known as c.420G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 420. The glutamic acid at codon 140 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 3 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This variant has been reported in multiple individuals with familial hypercholesterolemia (FH) (Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11; Chmara M et al, J. Appl. Genet. 2010 ; 51(1):95-106; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). Internal structural analysis indicates that this alteration results in disruption of the structurally critical Ca-binding SDE motif (Fisher C et al. Mol. Cell, 2006 Apr;22:277-83; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;H
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.68
MutPred		0.98		Loss of glycosylation at S142 (P = 0.1399);Loss of glycosylation at S142 (P = 0.1399);.;Loss of glycosylation at S142 (P = 0.1399);
MVP		1.0
MPC		0.77
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879254520; hg19: chr19-11216002;